Abstract：
Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.
摘要：
丁草胺在世界各地的农业中广泛使用，因此由于持久性和较差的生物降解性而对环境和公共卫生造成危害。铁凋亡是一种由谷胱甘肽（GSH）和GPX4抑制控制的铁介导的细胞死亡。P62是一种必需的自噬适配器，它调节Keap1激活核因子红系2相关因子2（Nrf2），有效抑制脂质过氧化，从而缓解铁性凋亡。这里,我们发现丁草胺引起脾巨噬细胞结构的改变，特别是线粒体形态受损，结构紊乱，这暗示了铁性死亡的发生。铁代谢的检测进一步证实了这一点，GSH系统,和脂质过氧化。机械上,丁草胺抑制p62的蛋白质水平并促进Keap1介导的Nrf2降解，从而导致GPX4表达降低并加速脾巨噬细胞铁凋亡。这些发现表明靶向p62-Nrf2-GPX4信号轴可能是治疗炎性疾病的有希望的策略。
